This invention relates to the synthesis of organic and inorganic chemical compounds and more particularly to an improved reaction block assembly for the manual and automated execution of solid and solution phase chemical processes of all types.
Discovery of new chemical compounds is at the core of many research and development efforts. A typical discovery research cycle involves multiple steps being conducted in a repetitive fashion. This initiates with the design of an experiment or series of experiments, execution of the experiment(s), analysis and evaluation of the results obtained, followed by design of another experiment or set of experiments. This cycle is repeated until the optimal desired result is attained. Scientists are continually searching for more efficient methods and procedures to aid in their research programs. Recently, the development of combinatorial chemistry concepts has initiated new approaches towards all aspects of the discovery process, in particular synthesis. The basis of combinatorial concepts is to enable the rapid, or high throughput, preparation of many different chemical compounds or formulations of chemical compounds, then investigate them, again in a rapid manner, for a particular desired property. This property could be biological activity, superconductivity, or the ability to catalyze another chemical transformation, as well as many others. The primary goal of combinatorial approaches is to speed up the discovery cycle and thereby result in more rapid achievement of desired results. These approaches, although relatively new, are finding applications in an ever-expanding realm. These efforts are now being directed towards a wide range of scientific fields including, but not limited to, pharmaceuticals, agrochemicals, catalysts, polymers, inorganic materials, flavors, fragrances, cosmetics and even process research.
Towards the realization of combinatorial concepts in practice, a number of tools have been developed to help achieve rapid and efficient processing. Among these are those that have been termed reaction blocks. Although many such devices have been tested, in general all possess some inherent limitations in terms of the reaction processes which can be performed in them. Among these limitations are:
(i) the materials utilized in the device are not compatible with certain chemicals or reaction conditions;
(ii) the reaction block cannot attain the temperatures required for the conduct of the widest variety of chemistry;
(iii) the standard reaction technique called reflux is not supported;
(iv) pressure cannot be created within the reactor as this will cause the contents to prematurely discharge;
(v) gas reagents cannot be utilized;
(vi) cross-contamination can occur between the individual reaction wells within a reactor;
(vii) a great deal of manual manipulation is required in order to properly utilize them in start to finish reaction processing;
(viii) those that are suitable for manual processing are not compatible with fully automated systems;
(viv) many are more suitable for only solution phase or only solid phase chemical processes rather than both;
(x) the physical configuration is not compatible with the requirements of further analytical techniques and the testing procedures utilized;
(xi) recovery of products from the device is not easily achieved or requires additional manual intervention.
Since the realm of potential chemical applications is so broad, a device in which any desired chemical reaction or transformation could be conducted is highly preferable. However, prior to this invention, no reaction block generally applicable to all types of chemical processes has been realized. Generally in order to achieve the rapid sample processing inherent in the conduct of combinatorial approaches, automation is adopted to assist wherever possible with the individual stages of the discovery cycle. However, in chemistry, particularly in synthesis, scientists often prefer to perform initial work manually, or with a minimal amount of automation. This allows them to more closely and immediately control, monitor and observe experimentation, which can often be critical to devising successful results. Once this initial chemistry development is completed, however, the next phases of study, often involving the conduct of larger numbers of experiments, such as syntheses, are most efficiently performed with the aid of automated systems. The ability to be able to directly transfer chemistry from the initial development stage to later stages is greatly enhanced by utilization of the same reaction block technology in each stage. Further, although chemists may wish to employ a reaction block in a manual manner, for some reaction blocks, manual intervention is required in order to utilize them. It would be desirable that this choice be left to the scientist. Preference would be given to a reaction block assembly that could be utilized in both for manual procedures and those involving automation, such as robotics.
For biological evaluation, a particular mechanical configuration has been adopted as a standard, that of the 96 well microplate. It is therefore highly desirable to be able to either conduct chemical experiments that are directed at finding biological activity in this configuration or in a format that can be easily or directly transferred to this configuration. For most other types of chemical investigation, such a standard does not currently exist and a wide variety of analysis configurations are employed. It is therefore also desirable that products can be easily transferred into any other configuration required.
A vast amount of chemical experimentation can be conducted at ambient temperatures and pressures. However, many chemical reactions and transformations and processing steps require extremes of temperature and pressure. In particular, reaction block technology has not been able to provide the ability to conduct reactions under pressure or with gaseous reagents. This is limiting as several very common chemical processes, such as hydrogenation or dissolving metal reductions, require handling of gases. It is desirable that a reaction block be able to operate in and withstand high and low temperatures as well as high and low pressures. Similarly, the ability to perform reflux applications is important. Although the advent of accurate alternative temperature control methods makes the use of reflux unnecessary in many cases, the chemist remains very comfortable with this standard technique and requires that any reactor have an appropriate condenser function to permit its application. This is particularly critical in the solution phase methodologies described later. In testing of chemical materials, as high a degree of purity as can be achieved is typically required for the analysis results to be properly interpreted. Therefore, when a reaction block contains multiple wells for the conduct of individual reactions, cross-contamination between them must be prevented.
Traditional chemistry is conducted by adding materials together in a particular manner which will undergo some type of transformation, typically in a liquid solvent medium. This has also been termed solution phase chemistry. Alternatively, reactions can be conducted at least partially with one or more of the reactants attached to an insoluble polymer support. A number of advantages are conveyed by this type of solid phase process, in particular speed of processing, ability to achieve complete transformation through the use of excess reactants and reagents (which usually result in material of higher purity) and amenability to automation. Indeed, the use of solid phase chemistry helped revolutionize peptide and oligonucleotide research by providing efficient access to synthetic material for research investigations. Likewise, these advantages have made use of solid phase chemistry techniques common in combinatorial approaches. However, not all chemical transformations can be conducted on solid phase, and the familiarity of many chemists with this technique is much lower than the more traditional approaches. It is therefore desirable that a reaction block be able to efficiently conduct both solid and solution phase chemistry.
The present invention overcomes the foregoing limitations by providing an improved reaction block assembly capable of performing many types of chemical processes, including reactions involving gases and both solid and solution phase chemistries. The reaction block assembly of the present invention further allows for the conduct of chemical reactions, transformation and other processing at a wide range of temperature and pressure. The reaction block assembly includes a reaction block provided with reaction wells. The materials utilized in its construction are chemically inert and compatible with the same range of temperature and pressure. The reaction block assembly of the present invention is designed to avoid the problem of premature discharge of the reaction wells under pressure. Thus, gas reagents can be utilized when required. For reaction blocks with multiple wells, cross-contamination is eliminated. The identical reaction block assembly can be utilized in a manual fashion as well as in semi and fully automated systems. It allows complete start to finish reaction processing when desired. The conduct of both solution phase and solid phase chemical processes is allowed. The reaction block assembly provides for direct transfer of products to any desired format upon conclusion of any given sequence of chemical steps.
More particularly, the block assembly of the invention comprises a reaction block in which are disposed a plurality of reaction wells. Influent and effluent ducts open at the upper face of the reaction block adjacent each of the reaction wells. These ducts provide communication between each reaction well and a source of reagents and gases and with waste removal means for removal of effluent from the reaction wells. A membrane sheet overlies the upper face of the reaction block and as explained in more detail below defines a first pneumatic valve at each of the reaction wells to control the input of reagents and gases and a second pneumatic valve to control effluent flow from the reaction well. The reaction block assembly preferably includes a temperature control block that underlies the reaction block for control of the temperature in the reaction wells. A waste block underlies the reaction block or, if used, the temperature control block. Waste ducts from the reaction wells communicate with the waste block for removal of reaction well effluent from the reaction block assembly.
Overlying the reaction block is a top manifold plate block for delivery of high pressure gas. The high pressure gas is utilized to actuate the pneumatic valves by applying pressure against the membrane to seal the influent duct and the effluent duct openings. Releasing the high pressure allows the pneumatic valves to be opened by relieving the positive pressure on the membrane further assisted by the reverse pressure of the ingredients acted upon by the charging gas introduced into the reaction wells to discharge the fluid contents of the wells. The membrane for opening and closing the pneumatic valves and a septum are disposed between the gas manifold top plate and the upper face of the reaction block. The openings of the reaction wells are closed by caps which are liquid and gas impermeable and they are adapted to be penetrated by a probe for delivery of reagents to the reaction wells. The septum serves to retain pressure in the reaction wells.
The reaction block is composed of a chemically inert, mechanically rigid material capable of being machined. The bottom of each reaction well is individually fitted with an inline filter for accommodation of solid phase chemical resins. The tops of the wells are fitted with caps to minimize contact by chemical vapors between the reaction wells and the septum, thus preventing corrosion of the septum and leaching of materials from the septum. The caps are preferably self sealing to reseal after accepting a probe for the delivery and aspiration of liquid reagents and solvents or aspiration of ingredients from the reaction wells.